The prevalence of benign breast disease and the substantial risk of breast cancer experienced by women with atypical hyperplasia makes our efforts to understand the biology of this relationship a high priority. We hypothesize that the relation between duration of use of postmenopausal hormones and risk of breast cancer is stronger among women with than without atypical hyperplasia; the expression of estrogen receptor activity is higher among women with atypia than among those with non-proliferative disease; retinoid-x receptor is expressed by a higher proportion of women with proliferative benign lesions. This new component of the study using blocks from the cases and controls to assess expression of receptors will further our understanding of the biologic mechanisms for the progression of benign lesions to breast cancer. Centralized histopathology reviews by expert breast histopathologists apply standard criteria. The extension of case accrual through the year 2000 will add 218 cases of breast cancer and 873 controls. This will give a final data set containing over 600 cases and 2500 controls. Overall, blocks will be available from 358 cases and using 2 controls per case (716 controls) to evaluate receptor status. Drs. Graham Colditz, Stuart Schnitt, and James Connolly have collaborated over the past decade to build this large histopathology resource and to evaluate categories of benign change in relation to risk of subsequent breast cancer. The Nurses' Health Study research group provides a rich resource of investigators to critically appraise the proposed research as it moves forward. This study is a key component of the Risk Identification and Risk Reduction Program within the Harvard Comprehensive Cancer Center/Dana Farber Cancer Institute.